Sjö, Lena Börjesson

ObjectiveIn the phase 3 head‐to‐head MANDARA study (NCT04157348), benralizumab demonstrated noninferiority to mepolizumab in inducing remission (defined as Birmingham Vasculitis Activity Score [BVAS] of 0 and oral glucocorticoid [OGC] dosage ≤4 mg/day at weeks 36 and 48) in patients with eosinophilic granulomatosis with polyangiitis (EGPA). This analysis investigated a more stringent definition of remission that included discontinuation of OGCs and being relapse‐free.MethodsPatients aged ≥18 years with documented relapsing or refractory EGPA receiving OGCs at ≥7.5 mg/day with or without immunosuppressive therapy for ≥4 weeks before enrollment were randomized (1:1) to benralizumab at 30 mg or mepolizumab at 300 mg subcutaneously every 4 weeks for 52 weeks. The proportion of patients achieving remission off OGCs, defined as BVAS of 0, OGC dose of 0 mg/day (at weeks 36 and 48) and no relapses during the double‐masked period, was assessed.ResultsPatients (n = 140) were randomized to benralizumab (n = 70) or mepolizumab (n = 70). The adjusted percentage of patients with remission off OGCs was 23.5% (n = 16) with benralizumab versus 11.1% (n = 8) with mepolizumab (difference 12.47 [95% confidence interval 0.46–24.48], P = 0.042). Of those who achieved remission off OGCs, 100% of benralizumab‐treated patients and 98.6% of mepolizumab‐treated patients achieved remission within the first 36 weeks of treatment.ConclusionThe administration of anti–interleukin‐5/receptor (IL‐5/R) therapies, benralizumab and mepolizumab, enable discontinuation of OGCs in some patients with EGPA, while avoiding relapses. These findings suggest that adding anti‐IL‐5/R therapy to standard primary treatment for patients with EGPA may improve response.

Abstract Rationale: The 1-year double-blind period of the MANDARA trial (NCT04157348) demonstrated non-inferiority of benralizumab to mepolizumab for achieving remission, in adults with relapsing/refractory eosinophilic granulomatosis with polyangiitis (EGPA). Here, we report the 2-year combined double-blind and ongoing open-label extension (OLE) data. Methods: On completion of the double-blind period (n=136/140) comparing benralizumab 1x30mg versus mepolizumab 3x100mg subcutaneously every 4 weeks, patients were invited to enter the OLE where they continued benralizumab (benra/benra) or switched from mepolizumab to benralizumab (mepo/benra). Endpoints included remission (Birmingham Vasculitis Activity Score=0 and oral glucocorticoid [OGC[ dose ≤4 mg/day), OGC use, relapse, blood eosinophil count (bEOS), Asthma Control Questionnaire (ACQ-6), pre-bronchodilator forced expiratory volume in 1 second (pre-BD FEV1), and safety. Results: In total, 128 patients entered the OLE (n=66 benra/benra, n=62 mepo/benra; mean age 52.8 years; 60.2% female), and 119 completed OLE Year 1. Baseline characteristics of those entering the OLE were similar to the double-blind period. At Week 104, over 60% in both groups (41 [62.1%] benra/benra and 42 [67.7%] mepo/benra patients) achieved remission. During the OLE, 51 (77.3%) benra/benra and 42 (67.7%) mepo/benra patients had no relapses. The percentage of benra/benra patients who discontinued OGCs was similar at Weeks 49-52 (27 [40.9%]) and Weeks 101-104 (29 [43.9%]), while the percentage increased for mepo/benra patients between Weeks 49-52 (16 [25.8%]) and Weeks 101-104 (27 [43.5%]; Figure). The median (IQR) OGC dose at Weeks 101-104 was 0.5 (0,5) in benra/benra and 1.36 (0,5) mg/day in mepo/benra patients. The median (IQR) bEOS in benra/benra patients was 20 (10,40) cells/µL at both Weeks 52 and 100; bEOS were depleted in mepo/benra patients from 70 (40,90) cells/µL to 20 (10,50) cells/µL by 4 weeks after switching. Mean (SD) ACQ-6 scores were 0.64 (0.78) in benra/benra patients and 0.60 (0.76) in mepo/benra patients at Week 104 compared with 1.39 (1.18) and 1.11 (0.95) at baseline. Mean (SD) pre-BD FEV1 was 2.59 (0.90) L versus 2.62 (0.84) L in benra/benra versus mepo/benra patients at Week 52, and 2.61 (0.90) versus 2.63 (0.81) L, at Week 100. Safety of mepolizumab and benralizumab was consistent with their known profiles. Conclusions: In patients with EGPA receiving benralizumab, remission rates, OGC discontinuation, and bEOS depletion were durable over 104 weeks with low relapse rates, and without loss of asthma control or lung function decline. Additional bEOS depletion and OGC sparing was observed in patients switching from mepolizumab to benralizumab.